Original Article
Comparative effectiveness of ledipasvir/sofosbuvir ± ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin in 6961 genotype 1 patients treated in routine medical practice
author notes Corresponding author1.Department of Veterans Affairs, Population Health Services, Palo Alto Health Care System, Palo Alto, CA, USA
First published: 13 June 2016
Full publication history •DOI: 10.1111/apt.13696
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Summary
Background Real-world data are needed to inform hepatitis C virus (HCV) treatment decisions.
Aim
Methods
Results 6961 patients initiated LDV/SOF (N = 4478), LDV/SOF + RBV (N = 1269), OPrD (N = 297), and OPrD + RBV (N = 917) at 126 facilities. Intention-to-treat SVR rates were 91.4% (3813/4170) for LDV/SOF, 90.0% (1098/1220) for LDV/SOF + RBV, 95.1% (269/283) for OPrD and 85.8% (746/869) for OPrD + RBV. SVR rates in those completing 8 weeks of LDV/SOF were 91.7% (1223/1333) and 12 weeks of LDV/SOF 94.6% (2475/2615), LDV/SOF + RBV 92.2% (1033/1120), OPrD 98.0% (248/253) and OPrD + RBV 95.5% (705/738). Significant predictors of SVR were African American race (OR 0.71, 95%CI 0.59–0.86, P < 0.001), body mass index (BMI) > 30 kg/m2 (OR 0.73, 95% CI 0.60–0.89, P = 0.002), FIB4 > 3.25 (OR 0.60, 95% CI 0.49–0.72, P < 0.001), OPrD + RBV compared to LDV/SOF (OR 0.60, 95% CI 0.48–0.76, P < 0.001) and subtype 1b (OR 1.38, 95% CI 1.11–1.71, P = 0.003). For those completing 12 weeks, FIB-4 > 3.25 and high BMI remained significant predictors.
significant, when limited to patients completing a 12-week course.
Ledipasvir/sofosbuvir (LDV/SOF) and ombitasvir/paritaprevir/ritonavir plus dasabuvir (OPrD) have been extensively evaluated individually in clinical trials of HCV-infected adults. The SVR rates in LDV/SOF trials of genotype 1 patients with and without cirrhosis ranged from 94% to 99% and in OPrD trials SVR rates ranged from 89% to 99%.[7-14] While these outcomes appear similar, differences in study design and patient populations prevent direct cross-study comparison of results.
Hepatitis C virus disproportionally affects the veteran population and the Department of Veterans Affairs (VA) is the largest US provider of healthcare to HCV-infected individuals caring for nearly 5% of all individuals in the US with HCV infection.[15, 16] Thus, ongoing evaluation of the effectiveness of HCV antiviral regimens remains a priority for VA.[17] With the rapid uptake of all-oral HCV regimens across the VA system and the diverse HCV-infected veteran population receiving these regimens, we examined SVR rates and comparative effectiveness of LDV/SOF ± ribavirin (RBV) vs. OPrD ± RBV in genotype 1 HCV-infected veterans treated in routine medical practice.
Eligible subjects included all genotype 1 HCV-infected veterans from any VA facility nationwide who initiated 8 or 12 weeks of VA-prescribed LDV/SOF ± RBV or 12 weeks of OPrD ± RBV by 31 March 2015 with an end of treatment (EOT) by 14 July 2015 and a days supply less than or equal to 91 days. For patients who received multiple courses of therapy, only the first course was included. The choice of regimen and timing of follow-up visits and laboratory testing was at the discretion of the provider as patients were treated in routine practice. The present cohort includes 4356 treatment naïve patients treated with LDV/SOF ± RBV who were reported on previously.[19] Patients were excluded if they changed regimens without a treatment interruption (n = 64), had a baseline HCV RNA ≤1000 IU/mL (n = 218), had a liver transplant (n = 141), or had genotype subtype 1a and received OPrD without RBV (n = 16).
In VA, HCV antiviral prescriptions are frequently filled for quantities less than 28 days. Patients were considered to have completed 8 weeks of LDV/SOF if they had received between 49 and 63 days’ worth of medication and 12 weeks LDV/SOF ± RBV or OPrD ± RBV if they received between 77 and 91 days’ worth of medication.
For all comparisons, a P < 0.01 was considered statistically significant. All analyses were performed using R version 3.1 (R Foundation for Statistical Computing, Vienna, Austria).
The protocol was approved by the Stanford University Institutional Review Board and the VA Palo Alto Health Care System Research and Development Committee.
Baseline characteristics for the cohort by regimen appear in Table 1. For the cohort, 64.3% (n = 4478) received LDV/SOF, 18.2% (n = 1269) received LDV/SOF + RBV, 4.3% (n = 297) received OPrD and 13.2% (n = 917) received OPrD + RBV. Patients who received LDV/SOF+RBV were most likely to be treatment-experienced and to have markers of advanced liver disease including a history of decompensated liver disease, lower mean platelet count, higher mean FIB-4 score, and FIB-4 > 3.25.
| Genotype 1 cohort (N = 6961) | LDV/SOF (N = 4478) | LDV/SOF + RBV (N = 1269) | OPrD (N = 297) | OPrD + RBV (N = 917) | |
|---|---|---|---|---|---|
| |||||
| Age (years) | 61.4 ± 6.2 (24.5–90.8) | 61.2 ± 6.5 (25.3–90.8) | 61.9 ± 5.2 (24.5–86.2) | 62.3 ± 5.9 (28.5–77.2) | 61.5 ± 6.0 (26.7–85.3) |
| Gender, male | 96.3 (6703) | 95.9 (4295) | 97.2 (1233) | 96.3 (286) | 96.9 (889) |
| Race/ethnicity | |||||
| African-American | 36.0 (2506) | 38.2 (1712) | 29.0 (368) | 46.8 (139) | 31.3 (287) |
| Caucasian | 51.6 (3591) | 50.5 (2263) | 54.5 (692) | 43.4 (129) | 55.3 (507) |
| Hispanic | 5.4 (376) | 4.5 (304) | 8.0 (102) | 4.0 (12) | 6.4 (59) |
| Other/multiple | 7.0 (488) | 6.7 (300) | 8.4 (107) | 5.7 (17) | 7.0 (64) |
| Diabetes | 31.5 (2195) | 30.3 (1357) | 37.7 (479) | 33.3 (99) | 28.4 (260) |
| Proton pump inhibitor | 27.7 (1927) | 26.3 (1178) | 35.4 (449) | 25.3 (75) | 24.5 (225) |
| HIV coinfected | 4.5 (310) | 5.3 (237) | 3.7 (47) | 2.4 (7) | 2.1 (19) |
| Decompensated liver disease | 3.2 (224) | 1.9 (87) | 8.6 (109) | 0.7 (2) | 2.8 (26) |
| Any treatment experience | 23.6 (1645) | 16.0 (718) | 53.0 (673) | 19.2 (57) | 21.5 (197) |
| DAA experience (% of treatment experienced) | 44.1 (726) | 39.1 (281) | 62.4 (420) | 7.0 (4) | 10.7 (21) |
| Prior SOF + simeprevir (n)* | 71 | 12 | 57 | 0 | 2 |
| Prior SOF + PEG + RBV or SOF + RBV (n)* | 131 | 29 | 96 | 0 | 6 |
| Prior boceprevir (n)* | 494 | 222 | 253 | 4 | 15 |
| Prior telaprevir (n)* | 74 | 21 | 53 | 0 | 0 |
| Prior treatment response | N = 1645 | N = 718 | N = 673 | N = 57 | N = 197 |
| Relapse | 29.9 (492) | 24.0 (172) | 39.2 (264) | 14.0 (8) | 24.4 (48) |
| Partial | 10.2 (167) | 9.1 (65) | 10.1 (68) | 21.1 (12) | 11.2 (22) |
| Null | 11.3 (186) | 9.6 (69) | 11.1 (75) | 12.3 (7) | 17.8 (35) |
| Unknown | 48.6 (800) | 57.4 (412) | 39.5 (266) | 52.6 (30) | 46.7 (92) |
| BMI (kg/m2) | 28.8 ± 5.3 (15.8–65.2) | 28.5 ± 5.2 (15.8–65.2) | 30.0 ± 5.5 (16.4–60.1) | 28.2 ± 5.0 (16.0–53.7) | 28.8 ± 5.3 (17.6–58.5) |
| BMI (kg/m2) | |||||
| <25 | 23.1 (1605) | 24.8 (1109) | 17.9 (227) | 24.2 (72) | 21.5 (197) |
| 25–29 | 41.6 (2893) | 41.6 (1863) | 37.6 (477) | 49.8 (148) | 44.2 (405) |
| ≥30 | 35.4 (2463) | 33.6 (1506) | 44.5 (565) | 25.9 (77) | 34.4 (315) |
| ALT (U/L) | 74.1 ± 56.5 (8–659) | 71.4 ± 55.9 (8–659) | 80.3 ± 52.3 (13–445) | 62.6 ± 50.7 (13–552) | 82.4 ± 64.3 (11–560) |
| AST (U/L) | 64.4 ± 45.5 (6–614) | 60.5 ± 43 (6–614) | 76.6 ± 48.2 (11–503) | 50.6 ± 34.8 (14–322) | 70.4 ± 52.1 (13–499) |
| Platelets (Κ/μL) | 185.6 ± 69.9 (6–759) | 194.4 ± 68.2 (6–661) | 150.3 ± 67.9 (22–759) | 214.6 ± 59.6 (81–421) | 181.8 ± 66.7 (32–470) |
| FIB-4 | 3.2 ± 3.7 (0.1–185.0) | 2.8 ± 3.8 (0.1–185.0) | 4.7 ± 4.1 (0.5–34.7) | 2.0 ± 1.2 (0.3–10.0) | 3.3 ± 2.9 (0.4–27.3) |
| FIB-4 | N = 6936 | N = 4460 | N = 1267 | N = 296 | N = 913 |
| ≤3.25 | 70.5 (4889) | 76.4 (3406) | 47.8 (605) | 89.5 (265) | 67.1 (613) |
| >3.25 | 29.5 (2047) | 23.6 (1054) | 52.2 (662) | 10.5 (31) | 32.9 (300) |
| HCV RNA (log IU/mL) | 6.2 ± 0.7 (3.0–7.9) | 6.2 ± 0.7 (3.1–7.9) | 6.2 ± 0.7 (3.0–7.8) | 6.3 ± 0.6 (3.9–7.6) | 6.3 ± 0.7 (3.0–7.8) |
| HCV RNA (IU/mL) | |||||
| <6 000 000 | 82.0 (5705) | 82.7 (3705) | 84.6 (1073) | 76.8 (228) | 76.2 (699) |
| ≥6 000 000 | 18.0 (1256) | 17.3 (773) | 15.4 (196) | 23.2 (69) | 23.8 (218) |
| HCV subtype 1b | 27.3 (1897) | 24.2 (1085) | 23.4 (297) | 100.0 (297) | 23.8 (218) |
| IL28B polymorphism | N = 989 | N = 598 | N = 204 | N = 33 | N = 154 |
| CC | 20.3 (201) | 22.6 (135) | 15.2 (31) | 9.1 (3) | 20.8 (32) |
| CT | 54.0 (534) | 52.7 (315) | 58.3 (119) | 51.5 (17) | 53.9 (83) |
| TT | 25.7 (254) | 24.7 (148) | 26.5 (54) | 39.4 (13) | 25.3 (39) |
Among patients who received LDV/SOF, 3.6% (n = 159) discontinued treatment before 8 weeks, 32.7% (n = 1464) received 8 weeks, 1.7% (n = 77) discontinued treatment between 8 and 12 weeks and 62.0% (n = 2778) received 12 weeks. In total, 94.7% completed either an 8 or 12 week course. Among people who received LDV/SOF + RBV, 8.1% (103/1269) discontinued treatment prior to completing 12 weeks. Among patients who received OPrD or OPrD+RBV, 11.4% (34/297) and 15.2% (140/917) of patients, respectively, discontinued treatment prior to completing a 12 week course. Significantly more patients receiving OPrD + RBV discontinued treatment prior to completing a 12-week course compared to those receiving LDV/SOF + RBV (P < 0.001).
Sustained virological response results were available for 94.0% (n = 6542) of patients in the cohort, including 24 patients who died while on treatment or shortly after who were categorised as no SVR. Four hundred nineteen patients whose last HCV RNA was undetectable, but occurred while still on treatment (n = 123) or less than 10 weeks after the EOT (n = 296), were excluded from the SVR analysis. Three hundred five patients had an undetectable HCV RNA obtained 10–11 weeks after the EOT and were included in the SVR analysis for reasons described previously.
Among 4170 LDV/SOF patients 91.4% achieved SVR; among 1220 LDV/SOF + RBV patients 90.0% achieved SVR; among 283 OPrD patients 95.1% achieved SVR and among 869 OPrD + RBV patients 85.8% achieved SVR (Table 2). For patients who received LDV/SOF, the SVR rates differed statistically based on categories of race/ethnicity, BMI, and FIB-4. For patients who received LDV/SOF + RBV, the SVR rates differed statistically based on proton pump inhibitor use and FIB-4. No statistically significant differences in SVR were observed according to baseline patient characteristics among patients receiving either OPrD or OPrD + RBV, and responses were generally similar to that observed in the overall population. SVR data for treatment naïve and experienced patients by subgroup can be found in Table S1A and B.
(Table 2). SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens with durations of 12 weeks or less
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Table 3. SVR rates by regimen for genotype 1 patients receiving ledipasvir/sofosbuvir- or ombitasvir/paritaprevir/ritonavir plus dasabuvir-based regimens who received 8 or 12 weeks of LDV/SOF and 12 weeks of all other regimens
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| Intention-to-treat OR (95% CI), N = 6525 | Received 12 weeks OR (95% CI), N = 4720 | |
|---|---|---|
| ||
| Age <55 years (ref. 55–64) | 1.37 (0.98–1.94) | 1.36 (0.83–2.37) |
| Age ≥65 years (ref. 55–64) | 1.17 (0.96–1.43) | 1.26 (0.94–1.70) |
| Female (ref. Male) | 2.23 (1.26–4.38) | 2.51 (1.04–8.23) |
| African American (ref. Caucasian) | 0.71 (0.59–0.86)*** | 0.86 (0.64–1.14) |
| Hispanic (ref. Caucasian) | 0.77 (0.54–1.12) | 1.00 (0.59–1.81) |
| Other/multiple (ref. Caucasian) | 0.87 (0.62–1.23) | 0.81 (0.51–1.34) |
| Diabetes (ref. no diabetes) | 1.01 (0.83–1.22) | 1.08 (0.82–1.42) |
| Decompensated liver disease (ref. no) | 0.60 (0.41–0.90) | 0.87 (0.51–1.54) |
| Treatment experienced (ref. naïve) | 0.90 (0.73–1.11) | 0.90 (0.67–1.21) |
| BMI <25 kg/m2 (ref. 25–29 kg/m2) | 0.77 (0.61–0.96) | 0.99 (0.69–1.44) |
| BMI ≥30 kg/m2 (ref. 25–29 kg/m2) | 0.73 (0.60–0.89)** | 0.66 (0.49–0.88)** |
| FIB-4 > 3.25 (ref. ≤3.25) | 0.60 (0.49–0.72)*** | 0.46 (0.35–0.60)*** |
| HCV subtype 1b (ref. 1a†) | 1.38 (1.11–1.71)** | 1.44 (1.04–2.02) |
| LDV/SOF + RBV (ref. LDV/SOF) | 1.07 (0.84–1.37) | 0.87 (0.64–1.19) |
| OPrD (ref. LDV/SOF) | 1.27 (0.74–2.37) | 1.68 (0.71–4.93) |
| OPrD+RBV (ref. LDV/SOF) | 0.60 (0.48–0.76)*** | 1.22 (0.83–1.84) |
The current HCV treatment landscape remains complex despite increasingly more effective HCV regimens, with variability in outcomes for patients with previous treatment experience, genotype subtype, race, degree of underlying liver disease and other comorbid conditions.[7, 8, 13, 14, 22-24] Because of the large sample size in this cohort, we were able to do robust subgroup analyses to examine differences among these characteristics and identify where challenges remain.
Despite SVR rates higher than any previously reported among veterans with advanced liver disease, the presence of advanced liver disease as indicated by a FIB-4 score greater than 3.25 remained a significant negative predictor of response with an apparent impact for treatment naïve and treatment experienced patients and across all regimens.[5, 23, 25] Over 2000 patients with advanced liver disease were included in this cohort. In multivariate models, the presence of advanced liver disease predicted reduced odds of achieving SVR by 40% independent of treatment experience and regimen. Absolute SVR rates in treatment naïve patients were generally four to five percent lower in those with advanced liver disease compared to those without advanced liver disease for patients who received LDV/SOF (87.6% vs. 92.6%), who received LDV/SOF + RBV (90.0% vs. 94.7%), and who received OPrD (91.7% vs. 96.1%). Current AASLD/IDSA treatment guidelines and FDA labelling recommend LDV/SOF for 12 weeks in treatment naïve patients with cirrhosis based largely on data from 34 patients in the ION-1 trial.[7, 26, 27] However, our observation of SVR rate of 87.6% with LDV/SOF in 889 treatment naïve patients with FIB4 scores >3.25 indicate SVR rates with this regimen may be below the 90% bar for which all-oral regimen expectations have been set and other treatment options might need to be considered in such patients.
In treatment experienced patients with and without advanced liver disease, reductions of 5–8% in SVR rates were seen in patients who received LDV/SOF (85.5% vs. 93.5%), who received LDV/SOF + RBV (85.4% vs. 90.9%), and who received OPrD + RBV (82.1% vs. 89.6%). The reduced SVR rates in the low to mid-80s in treatment experienced patients with advanced liver disease in this study mirror the 86% and 82% SVR rates observed in ION-2 in treatment-experienced cirrhotic patients receiving 12 weeks of LDV/SOF and LDV/SOF + RBV respectively.[8] In the TURQUOISE-II study SVR rates were 87% and 95% in treatment experienced cirrhotic null responders treated for 12 and 24 weeks respectively with OPrD+RBV.[14] The large number of patients included in our study coupled with the similar results obtained from ION-2 and TURQUOISE-II suggest that lower SVR rates may be expected in cirrhotic patients and particularly treatment-experienced cirrhotic patients treated in routine clinical practice. Extended treatment of 24 weeks in such patients may be warranted to achieve higher SVR rates.
In this cohort, SVR data were available for over 2300 African Americans. Multivariate modelling indicated African American race was associated with a 29% reduction in the odds of SVR. This effect was observed in multivariate models of the overall cohort but not in models limited to patients completing a 12 week treatment course suggesting that the reduced odds of SVR for African Americans arose in large part from excess early treatment discontinuations and from diminished effectiveness of 8-week LDV/SOF in African Americans, which has also been observed in retrospective analyses of the ION clinical trials.[22] Numerically lower SVR rates were observed in African Americans compared to Caucasians treated with LDV/SOF, OPrD and OPrD+RBV. In patients who received a full 12 weeks of treatment, SVR rates in African Americans were higher than in the intention-to-treat analysis and the numeric differences in SVR rates between African Americans and Caucasians were diminished.
This study included over 2300 patients with a BMI at or above 30 kg/m2, and in the overall cohort those with high BMI were 27% less likely to achieve SVR. As one might expect, the effect of BMI on SVR was not dependent on whether the patient completed therapy and, as such, high BMI remained a negative predictor of response in those who completed a 12-week treatment course. For such patients, additional treatment options may need to be considered to optimise SVR rates.
Shorter 8 week regimens were widely used in treatment-naïve patients with baseline HCV RNA below 6 000 000 IU/mL without cirrhosis. We could only assess the use of 8 week LDV/SOF regimens in patients who completed therapy because we were unable to otherwise determine if the original provider intent was to treat for 8 or 12 weeks using the available electronic data. Although the difference in SVR rates between those who completed 8 weeks and those who completed 12 weeks was numerically small at 3.4% it was statistically significant suggesting that to optimise a patient's likelihood of SVR the 12-week duration may be preferred.
Real-world SVR rates achieved with these treatment regimens were remarkably high. The large differences between real-world effectiveness and clinical trial efficacy previously observed with HCV antiviral treatment have now been almost eliminated with the use of potent all-oral regimens. Most of the small decrement in observed effectiveness in this real-world cohort may be explained in large part by higher early discontinuation rates. Early discontinuations rates were highest in those receiving OPrD + RBV (15.2%), followed by OPrD (11.4%), LDV/SOF + RBV (8.1%) and LDV/SOF (5.3%). Clinical trials tend to have early discontinuation rates of less than 3%.[7-14] Higher early discontinuation rates had the greatest impact on SVR rates in those receiving OPrD + RBV with a nearly 10% difference in SVR rates comparing intention-to-treat (85.8%) to those who completed 12 weeks (95.5%). While we did not examine reasons for early discontinuation, adverse effects and adherence are often recognised as contributing factors. Setting appropriate expectations about potential medication side effects and continued emphasis on adherence and persistence will remain important elements in maximising treatment success. Any remaining decrement in clinical effectiveness compared to clinical trial efficacy may be explained by differences in patient populations. For example, higher BMI in our cohort was identified as a significant negative predictor of SVR.
Given the high SVR rates achieved in clinical practice even among subgroups, regimen selection will depend increasingly upon nuanced considerations. Genotype subtype, presence of cirrhosis, prior treatment regimen or presence of pre-existing resistance associated polymorphisms currently determines the need for RBV and subsequent length of treatment for certain regimens. Potential for drug interactions and comorbidities may limit use of a particular agent. Enough options presently exist to allow providers some flexibility in selecting regimens tailored to meet individual patient characteristics or needs without sacrificing effectiveness. Expectations for high SVRs have been set and now validated in real-world cohorts, thus regimen subtleties together with cost considerations and insurance coverage will be key determinants for utilisation.
While this study includes one of the largest cohorts of diverse HCV-infected patients treated in clinical practice published to date, there are limitations. Specific reasons for early discontinuation (i.e. adverse events, poor tolerability, social or behavioural issues) could not be determined from the electronic data. Duration of treatment and early treatment discontinuation rates were determined based on the cumulative dispensed days’ supply which may overestimate the treatment duration as patients may have discontinued treatment even with medication in their possession. In VA, many prescriptions are filled for small quantities (e.g. 2-week supplies) which would limit the extent of the overestimation. Baseline resistance testing was not performed thus we were unable to assess the impact of this factor.
Author contributions: Drs Backus, Belperio, Loomis and Mole: Study concept and design. Drs Backus, Belperio, Shahoumian, Loomis and Mole: Analysis and interpretation of data; Drs Backus, Belperio: drafting of the manuscript, Drs Backus, Belperio and Mole: Critical revision of the manuscript for important intellectual content; Dr Shahoumian: Statistical analysis. This statement acknowledges that all authors approved the final version of the article, including the authorship list.
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